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Case Summaries & Options

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Thyroid Therapy

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Case Summaries & Options

Case SUMMARIES
  • First therapy available thyroid product approved by the FDA in 1939.
  • Porcine desiccated thyroid contains 4:1 ratio (to humans 11:1) of thyroid hormone.
  • Contains both liothyronine and levothyroxine in addition to trace amounts of other thyroid metabolites.
  • Considered a ‘natural’ source of thyroid hormones and alternative to synthetically derived hormones.
  • Evidence shows adequate absorption of thyroid hormone after administration.
  • The specifications for Thyroid USP powder require that each grain (1 grain = 64.7989mg or “60mg”) contains 34.2-41.8 mcg levothyroxine (T4) and 8.1-9.9 mcg liothyronine (T3) in order to produce a T4:T3 ratio of 4.22:1 to meet the stringent standards of the U.S. Pharmacopeia monograph, with a permissible variance of ± 10%16.
  • Desiccated thyroid is considered a safe alternative to levothyroxine. Patients lost more weight using desiccated. Hoang TD, et al. "Desiccated thyroid extract compared with levothyroxine in the treatment of hypothyroidism: a randomized, double-blind, crossover study." J Clin Endocrinol Metab. 2013 May;98(5):1982-90. doi: 10.1210/jc.2012-4107. Epub 2013 Mar 28.
  • Some patients prefer desiccated thyroid products and should be given the option if it makes them more comfortable and compliant to therapy, proven that there is a positive treatment outcome.
  • Most commonly recognized treatment is with levothyroxine (T4) monotherapy.
  • Levothyroxine provides adequate thyroid hormone replacement for a high percentage of patients evaluated across several studies.
  • Levothyroxine monotherapy has shown to be superior to liothyronine monotherapy. This is due to the sustained level of thyroid hormone achieved by levothyroxine resulting from its metabolism into downstream hormones (i.e. T3) over time.
  • Cases for combination therapy show a need to go beyond levothyroxine monotherapy in at least 20% of patients, revealing the inadequacy of levothyroxine monotherapy in patients who do not properly metabolize T4 into T3.
  • When T3 is used alone for hypothyroidism, it results in wide fluctuations of thyroid hormone levels. Exp Clin Endocrinol Diabetes. 2007 Apr;115(4):261-7. Twenty-four hour hormone profiles of TSH, Free T3 and free T4 in hypothyroid patients on combined T3/T4 therapy. Saravanan P1, Siddique H, Simmons DJ, Greenwood R, Dayan CM.
  • Sustained-Release T3 appears to mitigate serum hormone fluctuations experienced with Immediate-Release tablets.
  • Patients report improvement of symptoms when switched to a Sustained-Release T3 (from Immediate-Release)
  • Evidence suggests that extended-release versions of Thyroid USP, levothyroxine sodium, and liothyronine sodium can improve outcomes and life quality in patients. (Vu N, et al. ”Compounding Slow-Release Pharmaceuticals”. “International Journal of Pharmaceutical Compounding. 2009;13(2):144-5; “Hypothyroidism: Optimizing medication with Slow-Release Compounded thyroid Replacement.” International Journal of Pharmaceutical Compounding. 2005;9(4):268-273.)
  • “Development of a Sustained-Release T(3) preparation given as a single nighttime dose (together with levothyroxine once daily) might maintain physiological serum FT(4)-FT(3) ratio's throughout 24 h.” (Eur J Endocrinol. 2009 Dec;161(6):955-9. doi: 10.1530/EJE-09-0879. Epub 2009 Oct 6. Do we need still more trials on T4 and T3 combination therapy in hypothyroidism? Wiersinga WM1.)
  • Many prescribing physicians are following the evidence that indicates Extended-Release versions of Thyroid USP, levothyroxine sodium, and liothyronine sodium can provide certain patients superior results and an improved quality of life. (Vu N, et. al. ”Compounding Slow-Release Pharmaceuticals”. “International Journal of Pharmaceutical Compounding. 2009;13(2):144-5; “Hypothyroidism: Optimizing medication with Slow-Release Compounded thyroid Replacement.” International Journal of Pharmaceutical Compounding. 2005;9(4):268-273.)
  • Several studies have shown the potential benefit of combination therapy (Liothyronine sodium with levothyroxine sodium)( Nygaard B et. al. “Effect of combination therapy with thyroxine (T4) and 3,5,3’-triiodothyronine versus T4 monotherapy in patients with hypothyroidism, a double-blind, randomized cross-over study.” European Journal of Endocrinology. 2009;161(6):895-902; Bunevicius R, Kazanavicius G, Zalankevicius R, Prange AJ Jr. “Effects of thyroxine as compared with thyroxine plus triiodothyronine in patients with hypothyroidism. New England Journal of Medicine. 1999;340: 424
  • While others have found no difference* most of the studies that found no difference failed to mimic the physiological ratio of serum free T(4) (FT(4)) to free T(3) (FT(3)) concentrations, leaving them open to argument. *Nucl Med Commun. 2009 Aug;30(8):586-93. doi: 10.1097/MNM.0b013e32832c79e0. Thyroxine alone or thyroxine plus triiodothyronine replacement therapy for hypothyroidism.Ma C1, Xie J, Huang X, Wang G, Wang Y, Wang X, Zuo S. Wiersinga WM1.Eur J Endocrinol. 2009 Dec;161(6):955-9. doi: 10.1530/EJE-09-0879. Epub 2009 Oct 6.
  • Do we need still more trials on T4 and T3 combination therapy in hypothyroidism? 
  • Patients experience an improvement in their quality of life when switched from levothyroxine to a combination of levothyroxine with liothyronine: "Effects of Thyroxine as Compared with Thyroxine plus Triiodothyronine in Patients with Hypothyroidism" by Robertas Bunevicius, Gintautas Kazanavicius, Rimas Zalinkevicius, Arthur J Prange, Jr.
  • Evidence favors customized treatment for patients with DIO2 polymorphism. These patients have a reduced level of T3. J Clin Endocrinol Metab. 2017 May 1;102(5):1623-1630. doi: 10.1210/jc.2016-2587. DIO2 Thr92Ala Reduces Deiodinase-2 Activity and Serum-T3 Levels in Thyroid-Deficient Patients. Castagna MG1, Dentice M2, Cantara S1, Ambrosio R3, Maino F1, Porcelli T2, Marzocchi C1, Garbi C4, Pacini F1, Salvatore D2,5
  • Replacement therapy for hypothyroidism with thyroxine alone does not ensure euthyroidism in all tissues. Escobar-Morreale HF, Obregon MJ, Escobar del Rey F, Morreale de Escobar G
  • Only the combined treatment with thyroxine and triiodothryoidine ensures euthyroidism in all tissue. Escobar-Morreale HF, Escobar del Rey F, Obregon MJ, Morreale de Escobar G

Combination therapy and psychological function:

“Patients in whom long-term T4 therapy was substituted by the equivalent combination of T3 and T4 scored better in a variety of neuropsychological tests.” (Endocrine Abstracts (2002) 3 S40. T3/T4 combination therapy. Author: AD Toft)

Combination therapy needed for 20% of patients

“Athyreotic patients have a highly heterogeneous T3 production capacity from orally administered levothyroxine. More than 20% of these patients, despite normal TSH levels, do not maintain FT3 or FT4 values in the reference range, reflecting the inadequacy of peripheral deiodination to compensate for the absent T3 secretion. The long-term effects of chronic tissue exposure to abnormal T3/T4 ratio are unknown but a sensitive marker of target organ response to thyroid hormones (serum TSH) suggests that this condition causes an abnormal pituitary response. A more physiological treatment than levothyroxine monotherapy may be required in some hypothyroid patients” (Levothyroxine monotherapy cannot guarantee euthyroidism in all athyreotic patients 2011;6(8):e22552. doi: 10.1371/journal.pone.0022552. Epub 2011 Aug 1.)

Another case for combination therapy

“Although our professional organizations continue to recommend L-T4 alone for the treatment of hypothyroidism, the possibility of a D2 gene polymorphism should be considered in patients on L-T4 monotherapy who continue to complain of fatigue in spite of dosage achieving low normal serum thyroid stimulating hormone levels. A suggestive clue to the presence of this polymorphism could be a higher than normal free T4/free T3 ratio. Clinicians could consider adding T3 as a therapeutic trial in selected patients. Future well controlled clinical trials will be required to more fully resolve the controversy.” (Combination L-T3 and L-T4 therapy for hypothyroidism. Leonard Wartofsky MD)

Evidence supports the use of combination therapies in patients who:

  • Experience the inability to convert thyroxine to more active hormones including T3
  • Continue to experience symptoms on levothyroxine monotherapy
  • Experience depression, decline in cognitive function, and/or no improvement in life quality while on monotherapy.
  • Patients with genetic polymorphisms in deiodinase 2 and thyroid hormone transporters have been associated with well-being, fatigue, depression, and greater improvement on combination therapy.

Using Combination therapy to treat depression in hypothyroid patients:

Thyroid hormones, particularly triiodothyronine (T3), have long been used for the treatment of depression, most frequently to enhance the therapeutic activity of other antidepressants.

Genetic variations of the DIO2 gene associated with bi-polar disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2009 Aug 31;33(6):986-90. doi: 10.1016/j.pnpbp.2009.05.003. Epub 2009 May 7. Association of genetic polymorphisms in the type II deiodinase gene with bipolar disorder in a subset of Chinese population. He B1, Li J, Wang G, Ju W, Lu Y, Shi Y, He L, Zhong N

The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study evaluated the combination of T3 thyroid hormone and antidepressants in people who had not improved after two previous treatments. About 25% of those taking T3 thyroid hormone saw additional improvement in their symptoms.

Liothyronine for Depression: A Review and Guidance for Safety MonitoringInnov Clin Neurosci. 2017 Mar-Apr; 14(3-4): 24–29.Published online 2017 Apr 1.PMCID: PMC5451035

Liothyronine for Depression: A Review and Guidance for Safety Monitoring. Katie T.B. Touma, PharmD, BCPP, BCPS, Allysa M. Zoucha, PharmD, BCPP, and Jonathan R. Scarff, MD

Approximately 10% of hypothyroid patients are dissatisfied with the outcome of levothyroxine monotherapy. (Eur J Endocrinol. 2009 Dec;161(6):955-9. doi: 10.1530/EJE-09-0879. Epub 2009 Oct 6.Do we need still more trials on T4 and T3 combination therapy in hypothyroidism? Wiersinga WM1.) 

WHERE does my thyroid medication COME FROM?

The following products can only be sourced at a compounding pharmacy:
  • Customized thyroid hormone combinations
  • Sustained-Release thyroid hormones
  • Custom dosages of desiccated thyroid
  • Commercial products are sometime also available at a lower cost

Compounded thyroid medications are important for access

It is important to locate a high-quality compounding pharmacy that specializes in sterile and non-sterile medications used for hormone therapies, specifically thyroid hormone preparations. Sometimes more than one pharmacy is needed to source all medications; however, some pharmacies have a comprehensive catalog of thyroid medications including synthetic and desiccated products. Many of the commonly prescribed medications prescribed for thyroid and other hormone replacement therapies (HRT) are not available commercially, making a compounding pharmacy a valuable resource. Having options for commercial and compounded products allows for the personalized treatment necessary to provide the best outcome.

  • Compounding pharmacies use the same chemical ingredients used in non-compounded (commercial) products — Thyroid USP, Levothyroxine, Liothyronine.
  • Compounding gives prescribers complete control over dose composition and strength, binder, filler, and use of excipient alternatives.
  • Compounded thyroid products can be personalized to the specific patient and customized by the prescriber to include additional ingredients. Compounding allows for dosage options not available in commercial products.
  • Thyroid capsules can be compounded as an Immediate- or Extended-Release.
  • Many commercially manufactured thyroid medications are not covered by insurance, especially when a combination using multiple products is prescribed. The cost of a compounded medications is often significantly lower that commercial brand-name products, making them more accessible to patients who need ongoing treatment.
  • For patients requiring a combination of liothyronine and levothyroxine there are limited commercial product options. Compounding pharmacies can combine thyroid hormones into customized strength combinations.
  • The purpose of custom combination therapy and personalized compounding solutions is not meant to replace or declare superiority over the conventional treatments offered by the pharmaceutical industry. Compounded medication offers physicians and patients treatment options.

References: US Pharmacopeia Natural Formulary USP 37 N32 2014 Volume 3 May 1, 2014. The United States Pharmacopeial Convention. 2014.

Use of a compounded desiccated thyroid product vs commercial:

  • Desiccated Natural Thyroid — Thyroid USP — is available in several strengths only through compounding pharmacies.
  • The cost for commercial desiccated thyroid products including Armour has been increasing while product availability has been decreasing. Higher costs and frequent back-order status often makes commercial brand products harder to access for many patients.
  • Compounding pharmacies who specialize in custom hormone medications will compound thyroid capsules using the same USP desiccated porcine thyroid used in the commercial products, but often at a lower cost to the patient.
  • The specifications for Thyroid USP powder require that each grain contains 34.2-41.8 mcg levothyroxine (T4) and 8.1-9.9 mcg liothyronine (T3) in order to produce a T4:T3 ratio of 4.22:1 to meet the stringent standards of the U.S. Pharmacopeia monograph, with a permissible variance of ± 10% (US Pharmacopeia Natural Formulary USP 37 N32 2014 Volume 3 May 1, 2014. The United States Pharmacopeial Convention. 2014). Both commercial manufacturers and compounding pharmacies will adhere to these specifications.
  • The different commercial brands of thyroid USP contain other ingredients than just desiccated thyroid including fillers, dyes, binders, stabilizers, and excipients. Some of these compounds may be a concern for patients with allergies. (Women’s International Pharmacy. ”Thyroid Hormone Therapy Options”. 2014. Web; The United Pharmacopeial convention, USP 36 Official Monographs, Thyroid p 5383. December, 2013; Armour Thyroid (thyroid tablets) package insert. St. Louis, MO: Forest Pharmaceuticals, Inc.; 2011 Jan.) Compounding pharmacies typically use a gelatin capsule containing only desiccated thyroid and a natural cellulose filler.
  • Patients taking a unique dose of desiccated thyroid not available in commercial strengths can benefit from a custom compounded strength so that tablets do not have to be carefully split. 

Benefit of compounded sustained-release options:

  • No commercial sustained-release products available.
  • Available only at compounding pharmacies by prescription.
  • Usually in capsule form. Most commercially mass-produced thyroid drugs only offer an instant-release (IR) preparation containing a single hormone or USP Thyroid (see: package inserts for the 3 types of commercially manufactured products).
  • Compounding offers physicians the ability to prescribe sustained or extended release (SR) thyroid capsules. Compounders can usually make any type of thyroid product as an extended release capsule. Evidence suggests that extended-release versions of Thyroid USP, levothyroxine sodium, and liothyronine sodium can improve outcomes and life quality in patients. (Vu N, et al. ”Compounding Slow-Release Pharmaceuticals”. “International Journal of Pharmaceutical Compounding. 2009;13(2):144-5; “Hypothyroidism: Optimizing medication with Slow-Release Compounded thyroid Replacement.” International Journal of Pharmaceutical Compounding. 2005;9(4):268-273.)